The present invention relates generally to the field of ophthalmology. In particular, the invention relates to the treatment of ocular disorders including visual field loss and glaucoma using an isoquinolinesulfonyl compound, which lowers intraocular pressure (IOP) and produces dilation of ocular blood vessels.
Although the underlying causes of glaucoma are not fully understood at this time, glaucoma is characterized by damage to the optic nerve head, accompanied by a decrease in the normal visual field. One risk factor for glaucomatous visual field loss is elevated IOP. In fact, glaucoma has historically been treated by drug and/or surgical therapy to lower elevated IOP. While elevated IOP has been positively correlated with the rate of progression of visual field loss in glaucoma, visual field loss may occur at levels of IOP which are considered within the normal range. Thus, other factors, along or in addition to elevated IOP, may influence the occurrence and rate of progression of visual field loss.
To remain healthy and function normally, the retina and the optic nerve head fibers (neurons) must receive a proper supply of nutrients and oxygen, and must have their carbon dioxide and other metabolic waste products removed. This is accomplished by the microcirculation in these tissues. As used herein, the term xe2x80x9cmicrocirculationxe2x80x9d refers to the blood flow through the nutritive blood vessels, across whose walls nutrients, gases and waste products move. Blood flow to the eye depends upon the perfusion pressure (the systemic blood pressure minus the IOP). Some tissues have the ability to maintain (i.e., autoregulate) blood flow through a range of perfusion pressures such that an increase in systemic blood pressure may cause a reduction in the caliber of the blood vessel lumen. Conversely, reduction in systemic pressure in such tissues can result in vessel dilation; however, there is a point where perfusion pressure falls to such a level that the vessel is maximally dilated. Any further fall in perfusion pressure results in a reduction of blood flow to the tissue (ischemia). Ischemia may also result from obstruction, vasospasm, increased vascular resistance, or other interference with microcirculation. Prolonged ischemia ultimately can result in tissue necrosis or neuronal cellular apoptosis. In the case of the optic nerve head or retina, a state of visual dysfunction may precede the death of the neurons. Hence, if ischemia is involved in the death of optic nerve fibers due to glaucoma or some other ischemic-borne retinopathies or optic neuropathies, then its prevention could protect the neurons from death or loss of function.
The vasodilatory and spasmolytic activities of certain isoquinolinesulfonyl compounds have been described with respect to non-ocular tissues. See, e.g., EP 0 187 371 B1, which corresponds to U.S. Pat. No. 4,678,783. These vascular attributes are likely associated with inhibition of myosin-light chain kinase activity. Myosin-light chain kinase is an enzyme necessary for the excitation-contraction coupling of contractile activity in vascular smooth muscle. Inhibition of this enzyme results in vascular smooth muscle relaxation (i.e., vasodilation) which can product an increased blood flow.
The inventors believe that microcirculatory disturbances that restrict nutritive blood flow to the choroid, retina and optic nerve head are likely involved in the progression of visual field loss. While bound by no theories, the inventors postulate that compounds which enhance oxygen and nutrient delivery by enhancing ocular blood flow may be beneficial in preventing optic nerve head injury and may subsequently prevent or alter the rate of progression of visual field loss associated with glaucoma and ischemic optic neuropathies.
The present invention provided compositions and methods useful in the treatment of glaucoma (with or without ocular hypertension) and ocular ischemia, which may result in retinopathies and optic neuropathies. The compositions contain an isoquinolinesulfonyl compound which is effective in reducing or preventing optic nerve head or retinal damage as well as reducing IOP in man or other mammals toward normal levels and thus, in reducing or preventing visual field loss.
In an alternative embodiment of the compositions and methods of the present invention, the above compositions may further include a mucomimetic polymer, a gelling polysaccharide, a finely divided drug carrier substrate (defined below), or a combination of these components. These additional components provide compositions which enhance comfort and provide sustained release and delivery of the drug to the eye.